The use of platinum complexes such as cisplatin and carboplatin in cancer chemotherapy is well established in the art. A number of platinum complexes, such as cisplatin, are used to treat testicular, ovarian, head and neck and small-cell lung carcinomas. However, treatment with cisplatin may result in severe nephrotoxicity. A further clinical disadvantage is the problem of acquired drug resistance resulting in the tumour becoming refractory to treatment by the agent.
It is generally believed that platinum complexes such as cisplatin manifest their biological activity through covalent interaction with DNA. In particular, cisplatin induces the formation of a range of adducts on DNA including monodentate adducts, bidentate adducts, such as GG or AG and GNG intrastrand crosslinks [Reedijk et al., Structure and Bonding, (1987) 67, 53-89]. To a lesser extent, cisplatin also results in interstrand GG crosslinks and DNA-protein crosslinks [Rahmouni et al., Biochemistry, (1987) 26, 7229-7234]. These DNA lesions result in conformational changes which are reflected in bending and local unwinding of the DNA. These DNA lesions have been reported to inhibit the activity of various DNA polymerases [Vallan et al., Nucl. Acids Res., (1988) 16, 4407-4418; Pinto et al., Proc. Natl. Acad. Sci., (1985) 82, 4616-4619; Gralla et al., Cancer Res., (1987) 47, 5092-5096].
The interstrand crosslinks between two neighbouring guanine bases have also been shown to inhibit RNA polymerase function [Lemaire et al., Proc. Natl. Acad. Sci., (1991) 88, 1982-1985]. Accordingly, the cytotoxic effects of cisplatin are most likely attributable to the combined effects of these DNA lesions, rather than the result of any one specific lesion event.
Mono(platinum) and bis(platinum) complexes respectively containing one or two platinum atoms are known in the art (U.S. Pat. Nos. 4,225,529, 4,250,189, 4,533,502, 4565,884, 4,571,335 and 4,797,393). For example, mono(platinum) complexes include monomeric chloramine square-planar Pt(II) compounds which are four coordinate. The relative number of chloride and ammonia groups in such compounds may vary and these compounds may therefore be described by the general formula: EQU [PtCl.sub.m (NH.sub.3).sub.4-m ].sup.(2-m)+
Thus, the structure of these compounds may vary from [Pt(NH.sub.3).sub.4 ].sup.2+ where m=0 to PtCl.sub.4.sup.2- where m=4. Since Cl is more substitution labile in comparison to ammonia, the complexes [PtCl.sub.2 (NH.sub.3).sub.2 ] and [PtCl(NH.sub.3).sub.3 ]Cl are considered bifunctional and monofunctional, respectively, wherein the "bis" and "mono" prefixes refers to the number of leaving ligands. The charge of the complexes is obtained by considering that the Pt(II) cation has a formal charge of +2 and thus requires a negative charge of -2 for charge neutralization. For example, when m=0, neutralization is provided by the presence of two chloride anions outside the coordination sphere.
The formation of the bond between platinum and ammonia, which is a neutral ligand, may be described as electron-pair donation from NH.sub.3 to the empty orbitals on the Pt(II) atom. Thus, no electron sharing between the Pt and NH.sub.3 group takes place. Because of this absence of electron sharing, the number of neutral ligands does not affect the overall charge in the Pt coordination sphere. Thus [Pt(NH.sub.3).sub.4 ].sup.2+ is formally a 2+ cation requiring non-co-ordinating anion or anions, or counter-ions, having a net negative charge of 2- for neutralization of the complex. For example, neutralization can be provided by two mononegatively charged anions (e.g., NO.sub.3.sup.+, Cl.sup.-, PF.sub.6.sup.-, BF.sub.4.sup.- and mono-carboxylates having the general formula RCOO.sup.-) or a single dinegatively charged anion (e.g., SO.sub.4.sup.2-, dicarboxylates having the general formula [R(COO).sub.2 ].sup.2-). Therefore, for the same principles, [PtCl.sub.2 (NH.sub.3).sub.2 ] is a neutral complex.
These consideration can be applied not only to ammonia, but to neutral ligands such as primary or secondary amines as well.
It is noted that anionic ligands such as Cl.sup.- may be either co-ordinately bound (i.e., forming a Pt--Cl bond) or may act as a counter-anion without any need for covalent bond formation. The exact form that anions such as Cl.sup.- are comprised in a given platinum complex depends both on theoretical considerations (kinetic vs.thermodynamic effects) and the actual synthetic procedures utilised to make the complex (e.g., the extent of reaction, acidity, concentration of the particular anion, such as the concentration of Cl.sup.- which is contained in the reaction mixture. These considerations are applicable to other anionic and neutral ligands as well.
The fact that the overall charge of monoplatinum complexes depends on the relative number of neutral and anionic ligands which are bound to the Pt(II) metal is equally applicable for polynuclear complexes (which contain more than one Pt(II) coordinate spheres), and for Pt(IV) containing complexes wherein the oxidation state of the platinum moiety is 4+. For example, dinuclear complexes where two equivalent Pt(II) coordination spheres are linked by a diamine bridging agent may be represented by the general formula EQU [(PtCl.sub.m (NH.sub.3).sub.3-m).sub.2 (diamine)].sup.2(2-m)+
Thus, when m=2 and two bifunctional coordination spheres are present, the compound is neutral. In contrast, when m=1, only monofunctional coordination spheres are present and the platinum moiety has a formal charge of 2+ which must be counterbalanced by one or more counter-anions having a net charge of 2-.
Examples of trinuclear platinum complexes (also named tri-platinum complexes) were recently reported in literature [Yun Qu et al., Inorg. Chem., 32, 2591-2593 (1993)]. Said compounds, in which the ligands have a cis configuration, are complexes neutral or bearing an overall charge of 2+ and they can be represented by the following general formulae: ##STR1## in which X means a labile ligand (such as a chlorine atom) and R means an alkylene chain. From what stated above, it is evident that, in the case of the complexes with an overall charge of 2+, said charge is located on the central platinum atom, bearing four neutral ligands, whereas the two peripheral platinum atoms are formally neutral and, as defined above, bifunctional.